Acute Myeloid Leukemia

and Acute Complications

Brad Clifford
10/29/08 and 10/31/08

Objectives
Define AML and recognize the different subtypes
Recognize the common clinical presentation of a
patient with AML
Identify various prognostic factors in patients
with AML
Understand the different complications that are a
result of the disease and of treatment
Determine the therapy for these complications
Briefly understand the principles of treatment

Hematologic Malignancies
Lymphoid Cell Line (B or T cells)

ALL
CLL
Lymphoma
Myeloma

Myeloid Cell Line (granulocytes, monocytes, erythrocytes,

megakaryocytes)

CML
Polycythemia Vera
Essential Thrombocythemia
Myelofibrosis with metaplasia
Atypical chronic myeloid disorders
AML

Acute Myeloid Leukemia

What is it?
- Clonal expansion of myeloid precursor
cells with reduced capacity to differentiate
- As opposed to ALL/CLL, it is limited to
the myeloid cell line
differentiated from ALL based on morphology,
cytogenetics, cytochemical analysis, cell
surface markers

Myelopoiesis
Myeloid Progenitor cell Myeloblast
Promyelocyte Myelocyte
Metamyelocyte Band Granulocyte
Myeloid Progenitor cell Myeloblast
Monoblast Promonocyte Monocyte
Myeloid Progenitor cell Proerythroblast
Myeloid Progenitor cell Megakaryoblast

Epidemiology
Incidence 2.7 per 100,000
12.6 per 100,000 in those over 65 yo
median age of presentation : 65 yo

More prevalent:
Males
European descent
Hispanic/Latino background (promyelocytic
leukemia (AML M3))

Epidemiology
Increased incidence
Genetic fragility

Bloom syndrome
Faconi anemia
Wiskott Aldrich
Down, Klinefelter, Patau syndromes

tobacco use?
herbicides?, pesticides?
benzene exposure
XRT
Topoisomerase II inhibitors (e.g etopisode), alkylating agents
MDS
other cell proliferation disorders
CML, polycythemia vera, primary thrombocytosis, PNH

Clinical symptoms

Due to the excessive proliferation of

myeloid precursor cells in bone marrow,
certain symptoms/lab findings are
expected (e.g. as a result of
pancytopenia)
1. Functional neutropenia fever, chills
(INFECTION)
2. Thrombocytopenia bleeding, bruising
3. Anemia weakness, fatigue

Clinical symptoms
Other findings
bone pain (sternum, lower extremities)
infrequent but thought to be secondary to
expansion of medullary cavity

Physical Findings
Gingival involvement (especially in the
monocytic variants (M4 or M5))
Rare hepatosplenomegaly or LAD
Pallor, petechiae, ecchymoses
Bone tenderness
Retinal hemorrhage
CNS infiltration (more common in M4 and M5)
Skin, soft tissue infiltration

Gingival Infiltration in Monocytic

(AML M4 eos) Variant of AML

Mani, A, Lee, DA. Leukemic Gingival Infiltration. N Engl J Med 2008; 358(3): 274. Copyright 2008 Massachusetts Medical Society

Clinical symptoms/Physical
Findings
Extramedullary disease (ie, myeloid sarcoma)
Can also have involvement of lymph nodes, intestine,
mediastinum, ovaries, uterus

Diagnosis
Previously >30% blasts on BM aspirate
(per FAB criteria)
Recently changed to > 20% blasts on BM
aspirate (per WHO criteria)
patients with certain cytogenic abnormalities
are considered to have AML regardless of
blast percentage
t(8;21)(q22;q22), inversion (16)(p13q22)
t(16;16)(p13;q22), and t(15;17)(q22;q12)

FAB Classification of AML

M0 undifferentiated acute myeloblastic leukemia (5%)

M1 AML with minimal maturation (20%)
M2 AML with maturation (30%)
t(8;21)

M3 Acute promyelocytic leukemia (5%)

t(15;17)

M4 Acute myelomonocytic leukemia (20%)

M4 eos Acute myelomonocytic leukemia with eosinophilia (5%)
inv (16)

M5 Acute monocytic leukemia (10%)

t(9;11)

M6 Acute erythroid leukemia (3%)

M7 Acute megakaryoblastic leukemia (3%)

WHO Classification

AML with certain genetic abnormalities

AML with multilineage dysplasia (more than one abnormal myeloid cell type is
involved)
AML related to previous chemotherapy or radiation
AML not otherwise specified

t(8;21), t(16), inv(16), chromosome 11 changes

t(15;17) as usually seen with AML M3

undifferentiated AML (M0)

AML with minimal maturation (M1)
AML with maturation (M2)
acute myelomonocytic leukemia (M4)
acute monocytic leukemia (M5)
acute erythroid leukemia (M6)
acute megakaryoblastic leukemia (M7)
acute basophilic leukemia
acute panmyelosis with fibrosis
myeloid sarcoma (also known as granulocytic sarcoma or chloroma)

Undifferentiated or biphenotypic acute leukemias (leukemias that have both

lymphocytic and myeloid features. Sometimes called ALL with myeloid markers, AML
with lymphoid markers, or mixed lineage leukemias.)

AML M2

Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of tumor pathology (electronic fascicle), Third series, fascicle 9, 1994,
Washington, DC. Armed Forces Institute of Pathology.

AML M3 (Promyelocytic)

Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of tumor pathology (electronic fascicle), Third series, fascicle 9, 1994,
Washington, DC. Armed Forces Institute of Pathology.

AML M3 (Promyelocytic)

Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of tumor pathology (electronic fascicle), Third series, fascicle 9, 1994,
Washington, DC. Armed Forces Institute of Pathology.

AML M4 eos

From Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of tumor pathology (electronic fascicle), Third series, fascicle 9, 1994,
Washington, DC. Armed Forces Institute of Pathology.

Case #1

52 yo M no significant PMHx presents with general

malaise for several days, headache and shortness of
breath. Exam reveals palor and scattered petechiae.
Found to have 95,000 WBC with HCT of 22 and
platelet count of 22,000. Chem panel unremarkable.
Treatment of this condition would involve:
A)
B)
C)
D)

Induction chemotx with anthracycline/cytarabine

Leukapheresis
Transfusion of platelets, PRBCs followed by leukapheresis
Running throughout the hospital yelling as loudly as possible

Leukostasis
Leukostasis predominantly in those with WBC
counts > 100,000 (10% of patients); can also be
seen in patients with WBC > 50,000
Most common in those with M4 or M5 leukemia
Function of the blast cells being less deformable than
mature myeloid cells. As a result, intravascular plugs
develop.
High metabolic activity of blast cells and local
production of various cytokines contribute to
underlying hypoxia

Leukostasis in AML

Thornton, KA, Levis, M. FLT3 Mutation and Acute Myelogenous Leukemia with Leukostasis. N Engl J Med 2007; 357:1639. Copyright
2007 Massachusetts Medical Society

Leukostasis
Common symptoms
Pulmonary: dyspnea, chest pain
CNS: headaches, altered mentation, CN
palsies, ocular symptoms
Priapism
Myocardial Infarction

Leukostasis
Treatment
Chemotherapy with induction agents (e.g cytarabine,
anthracycline) or with high dose hydroxyurea
Consider low dose cranial irradiation to prevent cell
proliferation in the CNS (can see intracranial
hemorrhage in patients with leukostasis)
Avoid PRBC transfusion if possible as additional
blood elements contribute to the hyperviscosity
In patients that are unable to undergo immediate
chemotx (e.g renal insufficiency, metabolic
derangements, etc), leukapheresis is a 2nd option

Leukostasis
Leukapheresis
Limited affect on established vascular plugs
Limited benefit in those with underlying pulmonary
symptoms following chemotx. Symptoms in this case
related to leukocyte lysis and subsequent
inflammatory response
Should not be used as a single modality agent in
patients with leukostasis (unless chemotx is delayed)
May consider as adjunct to chemotx in patients with
WBC >100,000 and symptoms suggestive of
leukostasis

Leukapheresis
Bug G et al (2007) - Retrospective study from Germany
of 53 newly diagnosed cases of AML and
hyperleukocytosis. Cohort A Chemotx without
leukoreduction (28 patients). Cohort B Chemotx
followed by leukapheresis (25 patients).
By day 21 -> 13 of 53 patients had died with a lower risk of early
death in Cohort B compared to Cohort A (16% vs. 32%
respectively; p = 0.015).
Dyspnea (p = 0.005), elevated creatinine (p = 0.028), and higher
lactate dehydrogenase serum levels (p = 0.021) were
independent risk factors for early death.
At a median follow-up of 24.2 months, the overall survival was
similar in both cohorts (Cohort A, 7.5; Cohort B, 6.5 months).
(eg, Leukapheresis had no impact on long term survival)

Leukapheresis
Giles et al (2001) - 146 patients with
newly-diagnosed AML (APL excluded) and
an initial WBC count > 50 x 10(9)/L of
whom 71 underwent leukapheresis.
Pheresis reduced 2-week mortality rate (p = .
006)
No evidence that pheresis lengthened longerterm or overall survival; actually data to
suggest the opposite (p = .06)

Case #2
72 yo F initiating chemotx with intermediate dose
cytarabine. Develops progressive nausea and
lethargy with generalized muscle cramps. An
ECG is obtained. What diagnosis is
concerning?

Tumor Lysis Syndrome

Characterized by metabolic derangements
caused by massive release of cellular
components following lysis of malignant
cells
Commonly seen in malignancies with high
rates of cell proliferation (esp. ALL,
Burkitts lymphoma); also can be seen
with AML

Tumor Lysis Syndrome

Tumor lysis syndrome - hyperphosphatemia,
hyperkalemia, hyperuricemia, hypocalcemia and
uremia
Retrospective study of 788 patients (433 adults) found
incidence of hyperuricemia and TLS to be 14.7%/3.4%
in patients with AML compared to 21.4%/5.2% in
patients with ALL and 19.6%/6.1% in patients with NHL

Electrolyte abnormalities can occur without the

entire spectrum of TLS or even before tx is
initiated
Hyperuricemia
Lactic acidosis

Tumor Lysis Syndrome

Release of intracellular proteins catobilized to
hypoxanthine xanthine uric acid Crystalization of
uric acid and in renal tubules impaired renal function
Release of phosphate from malignant cells calcium
phosphate precipitation and further renal impairment
along with hypocalcemia and resultant symptoms from
Ca
Hyperphosphatemia: nausea, vomiting, diarrhea, seizures,
lethargy
Hypocalcemia: arrhythmia, hypotension, tetany, cramps
Hyperkalemia: arrhythmia, cramps, paresthesia

Tumor Lysis Syndrome

Prevention and management

IV hydration : promotes excretion of uric acid and phosphate; improves
renal blood flow/GFR
Allopurinol competitive inhibitor for xanthine oxidase. Therefore,
conversion of purine metabolites to uric acid
However, must consider buildup of xanthine crystals acute obstructive
uropathy (HYDRATE!!!)

Recominant urate oxidase (rasburicase)

Promotes conversion of uric acid to allantoin (highly soluble; urinary
excretion)
Indicated in patients at high risk of TLS (Burkitts Lymphoma, B-ALL, ALL
(WBC >100,000), AML (WBC >50,000)
Also indicated in patients that develop hyperuricemia despite allopurinol

Dialysis can be used in severe cases

Urine alkalization is NOT recommended does not increase solubility of
xanthine/hypoxanthine with an increased propensity to develop
xanthine-obstructive uropathies (esp with allopurinol use)

Case #3
A 30-year-old nulliparous female suffered
from placental abruption at the 25th week
of pregnancy, and emergent cesarean
section was done immediately with
termination of the pregnancy. Labs were
significant for a prolonged PTT/INR,
anemia, thrombocytopenia. Peripheral
smear as shown. What other tests would
you obtain and what is the likely
diagnosis?

Greer JP, Kinney MC. Acute nonlymphocytic leukemia. In: Lee GR, Bithell TC, Foerster J, et al, eds. Wintrobes
Clinical Hematology. 9th ed. Philadelphia, Pa: Lea & Febiger;1993:1920-1945.

AML M3 (Promyelocytic)

Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of tumor pathology (electronic fascicle), Third series, fascicle 9, 1994,
Washington, DC. Armed Forces Institute of Pathology.

DIC (Disseminated Intravascular

Coagulation)
Seen in AML M3 (promyelocytic)
Function of primary granules of promyelocytes
granules contain a thromboplastin-like substance
(initiates extrinsic coagulation pathway) and a factor X
and Xa activator
Initiation of coagulation cascade widespread
thrombin and fibrin deposition throughout vasculature
microangiopathic vasculopathy and inability of
liver/bone marrow to sustain coagulant/platelet levels
multi-organ damage with thrombocytopenia and
elevated PT/PTT
Excessive production of plasmin as well
breakdown of fibrin/fibrinogen to FDPs

Coagulation cascade

en.wikipedia.org/wiki/Tissue_factor

DIC

Common symptoms/findings
in addition to weakness (anemia), infections/fever (malfunctioning
WBCs)
petechiae, ecchymoses, hematuria, bleeding from venipuncture sites
migratory thrombophlebitis (Trousseaus syndrome)
nonbacterial thrombotic (marantic) endocarditis
DVT/PE

Lab findings

Prolonged PT/INR, PTT

microangiopathic anemia (schistocytes)
thrombocytopenia
elevated fibrin split products
elevated D-dimer
low fibrinogen

DIC

Treatment
Supportive therapy

1.

Platelets
Cryoprecipitate (fibrinogen)
FFP

Treatment for obvious thrombosis (e.g thrombophlebitis, mural

thrombus)

2.

UFH or LMWH; often resistant to coumadin

activated protein C

Treatment of underlying malignancy

3.

In the case of AML M3 All-Trans Retinoic Acid (PML-RAR)

Induces differentiation beyond promyelocyte phase

Only with the more common t(15;17) translocation; t(11;17) and t(5;17) do not
respond to ATRA

Remission rates of greater than 90% with AML M3 patient treated with
ATRA and chemotx (eg, anthracyclines (idarubicin)) with 60-70% disease
free survival
Arsenic trioxide in those that relapse achieves complete remission in
>90%

Treatment of DIC
Randomized prospective double-blind trial
(2002) from Japan comparing activated protein
C and unfractionated heparin for the treatment of
DIC. 132 patients with 63 receiving APC and 69
receiving UFH.
The effects on DIC-related organ dysfunction were
not significantly different between the 2 groups.
No significant difference in the rate of complete
recovery from DIC between the 2 groups.
The rate of death from any cause within 28 days after
treatment was 20.4% in the APC group, significantly
lower than the 40% death rate observed in the
heparin group (P < .05).

DIC

Side effects of ATRA therapy

1. Headache, bone pain, hypertriglyceridemia, dried
mucous membranes and skin
2. Retinoic Acid Syndrome (occur <20% of those tx
with ATRA)

thought to be caused by cytokine release and/or rapid

release of M3 promyelocytes from bone marrow following
ATRA therapy
fever, respiratory distress, hypotension, pleural and
pericardial effusions, LE edema, occasional renal failure
highly elevated WBC count = higher risk
prevent by tx with chemotx (eg, cytarabine) at same time;
also dexamethasone

CNS Involvement
Occurs in less than 5% of AML patients (highest
incidence in relapsed promyelocytic (M3)
variant)
Routine LP is not performed unless symptoms
suggestive of CNS pathology
Common symptoms
headache
mental status changes
CN palsies (commonly CN III or VI)

CSF findings
blast cells
moderate increase in protein and moderate decrease in
glucose

CNS Involvement
Treatment
Intrathecal chemotherapy (methotrexate or
cytarabine) +/- whole brain XRT
addition of XRT depends on response to
intrathecal chemotx and whether there is cranial
nerve involvement
high relapse rate

Commonly administer prophylactic intrathecal

chemotx in relapsed promyelocytic disease

Ocular Involvement
Seen in over 60% of newly diagnosed
AML patients
Commonly choroid and retina
(hemorrhage, cotton wool spots)
Can also involve conjunctiva and lacrimal
glands
Treatment with common induction
chemotherapeutic agents and with platelet
transfusions as needed

Other Complications
Necrotizing enterocolitis usually at time
of neutrophil nadir post chemotx
Joint involvement in setting of leukemic
blast synovial membrane infiltration
<4% of those with AML

Treatment of AML
Goal for complete remission
platelet count greater than 100
neutrophil count greater than 1000
BM with 5% or less blasts

Molecular complete remission : no evidence of

leukemic cells in BM even with sensitive tests
(eg, PCR, flow cytometry)
If in complete remission for >3 yrs without
relapse potentially cured (<10% chance of
relapse)

Treatment
Assess need for emergent therapy
APL with blast > 50,000 and evidence of DIC
leukemic crisis with organ dysfunction
(pulmonary, CNS) seen most often with M4
or M5 variant

Prognostic Factors in AML

Favorable

younger age (<50)

WBC <30,000
t(8;21) seen in >50% with AML M2
inv(16) seen in AML M4 eos
t(15;17) seen in >80% AML M3

Unfavorable

older age (>60)

Poor performance status
WBC >100,000
Elevated LDH
prior MDS or hematogic malignancy
CD34 positive phenotype, MRD1 postive phenotype
del (5), del (7)
trisomy 8
t(6;9), t(9;22)
t(9;11) seen in AML M5
FLT3 gene mutation (seen in 30% of patients)

Treatment

Remission induction therapy

Commonly anthracycline (ie, daunorubicin, idarubicin) and

cytarabine (3+7 regimen)

Cytarabine has ample CNS penetration so no need for

prophylactic intrathecal chemotx (also, risk in patients with AML
compared to ALL)
60-80% achieve complete remission

Postremission therapy
1. Consolidation

longer survival than maintence alone

typically high dose cytarabine

2. Maintenance continue chemotx monthly for 4-12 months

nonmyelosuppressive doses

Treatment
Increasingly, hematopoietic cell
transplantation is used in patients with
AML after 1st remission in those with
poor/intermediate prognostic factors.
Also allogenic/autologous transplant in
those with relapse or 2nd remission
autologous with higher relapse rates. Used in
those without HLA matched donor

Disease Free Survival

(EORTC/GIMEMA trial)

Zittoun, RA, Mandelli, F, Willemze, R, et al, N Engl J Med 1995; 332:217

Overall Survival
(EORTC/GIMEMA trial)

Zittoun, RA, Mandelli, F, Willemze, R, et al, N Engl J Med 1995; 332:217

Treatment
Standard therapy remission rates of 60-80% with
median remission durations of 1 yr
less than 20% achieve long-term remission free survival

Therapy is altered in older individuals (esp. those with

poor performance status)
AML believed to be a clinically/biologically distinct entity in older
individuals remission rates of 45% in those > 60 yo with less
than 10% long-term remission free survival
low dose cytarabine +/- hydroxyurea
investigational therapy
palliative care

Survival in AML

Jabbour EJ, Estery E, Kantarjian HM. Adult Acute Myeloid Leukemia. Mayo Clin Proc. 2006;81:247-260.

Treatment in Refractory or
Relapsed AML
Most important predictive factor for outcome in
relapsed/refractory AML = duration of 1st remission
Relapse is defined by >5% blasts in bone marrow
Salvage therapy produces remission rates of 40-60% in pts with
remission rates >1 yr, but only 10-15% in those with shorter
remission
Allogenic transplant appears superior to cytarabine based chemotx
in those with remission <1 yr

Gentuzumab (anti-CD33 Ab linked to antitumor antibiotic

calicheamicin) only approved tx for relapsed AML in pts >60 yo
with remission > 3 months

Treatment
Supportive care
G-CSF
platelet transfusions
PRBCs (leukodepleted, irradiated)
Prophylactic antibiotics
fluconazole (candidiasis)
acyclovir (HSV, VZV)

Future Therapeutic Targets

Surface antigens using monoclonal
antibodies
Signal transduction targeting (eg, FLT3,
methylation, angiogenesis)
Multidrug resistance reversing agents
Gene expression profiling

Resources

Andreoli et al. Acute Myelogenous Leukemia. Cecil Textbook of Medicine. 2004; 446-447.
Aoki N et el. A comparative double-blind randomized trial of activated protein C and
unfractionated heparin in the treatment of disseminated intravascular coagulation. Int J Hematol.
2002 Jun;75(5):540-7.
Bernard et al. Guidelines for the Management of Pediatric and Adult Tumor Lysis Syndrome: An
Evidence Based Review. Journal of Clinical Oncology. Vol 26. June 1 2008.
Bug G et al. Impact of leukapheresis on early death rate in adult acute myeloid leukemia
presenting with hyperleukocytosis. Transfusion. 2007 Oct;47(10):1843-50.
Estey E. Acute Myeloid Leukemia and Myelodysplastic Syndromes in Older Patients. Journal of
Clinical Oncology. Vol 25. May 10 2007.
Giles et al. Leuk Lymphoma. 2001 Jun;42(1-2):67-73.
Jabbour EJ, Estery E, Kantarjian HM. Adult Acute Myeloid Leukemia. Mayo Clin Proc.
2006;81:247-260.
Larson RA. Treatment of Acute Myeloid Leukemia in Younger Adults. Up to Date Online. June
11, 2008.
Lowenberg B, Downing J, Burnett A. Acute Myeloid Leukemia. NEJM. 1999;341:1051-1061.
Randolph T. Acute promyelocytic leukemia (AML M3) part 1. Clinical Laboratory Science,
Spring 2000; 13(2): 98-105.
Schiffer C. Complications of Acute Myeloid Leukemia. Up to Date Online. June 11, 2008.
Zittoun, RA, Mandelli, F, Willemze, R, et al, NEJM 1995; 332:217.